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作者 Stella S, Vitale SR, Martorana F, Massimino M, Pavone G, Lanzafame K, Bianca S, Barone C, Gorgone C, Fichera M, Manzella L
Stefania Stella, 1,2 Silvia Rita Vitale, 1,2 Federica Martorana, 1,2 Michele Massimino, 1,2 Giuliana Pavone, 3 Katia Lanzafame, 3 Sebastiano Bianca, 4 Chiara Barone, 5 Cristina Gorgone, 6 Marco Ficheraria, 1 Maperimental Clinic, 1 Maperimental Clinic, Maperimental Clinic University of Catania, Catania, 95123, Italy;2 Center for Experimental Oncology and Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania , 95123, Italy; 3 Medical Oncology, AOU Policlinico "G. Rodolico - San Marco", Catania, 95123, Italy; 4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Italy; 5 Mankhwala Genetics, ASP, Syracuse, 96100, Italy; 6 Dipatimenti ya Biomedical and Biotechnology Sciences, University of Catania, Medical Genetics, Catania, Italy, 95123; 7Oasi Research Institute-IRCS, Troina, 94018, Italy Communications: Stefania Stella, telefoni +39 095 378 1946, imelo [imelo yotetezedwa]; [imelo yotetezedwa] Cholinga: Kusintha kwa majeremusi mu BRCA1 ndi BRCA2 ndikukhazikitsa khansa ya m'mawere (BC), ovary (OC) ndi zina zomwe zimagwirizanitsidwa ndi chiopsezo cha moyo wonse wa khansa. Ngakhale kuti pali deta pamitundu yosiyanasiyana ya BRCA m'mabanja a Sicily, maphunziro okhudza anthu a kum'mawa kwa Sicily akusowa. index.RESULTS: Pazonse, odwala 35 (9%) anali ndi BRCA pathogenic variable, 17 (49%) mu BRCA1 ndi 18 (51%) mu BRCA2.BRCA1 zosintha ndizofala kwambiri mwa odwala atatu omwe alibe BC, pamene kusintha kwa BRCA2 kumakhala kofala kwambiri mu luminal BC odwala. proliferative index.Mapeto: Zomwe tapeza zimapereka chithunzithunzi cha BRCA mutational status mu BC odwala ochokera kummawa kwa Sicily ndikutsimikizira udindo wa NGS kusanthula pozindikira odwala omwe ali ndi cholowa cha BC.Ponseponse, detayi ikugwirizana ndi umboni wam'mbuyomu wotsimikizira kuti BRCA imayang'anira kupewa ndi kuchiza khansa muzitsulo zosinthika.
Khansara ya m'mawere (BC) ndi khansa yofala kwambiri padziko lonse lapansi komanso khansa yakufa kwambiri kwa amayi.1 Zomwe zimapangidwira zomwe zimatsimikizira kuti BC prognosis ndi khalidwe lachipatala zakhala zikuphunziridwa mozama ndipo zadziwika pang'ono pakapita nthawi.Zowona, zizindikiro zingapo zomwe zimagwiritsidwa ntchito pakalipano zimagwiritsidwa ntchito kuyika BC m'magulu osiyanasiyana a maselo.Iwo ndi estrogen (ER) ndi / kapena progesterone kukula kwaumunthu (Pgder2HER receptor) receptor (Pgder2HER receptor) kukulitsa, kuchuluka kwa chiwerengero cha Ki-67 ndi kalasi ya chotupa (G) .2 Kuphatikizika kwa mitunduyi kunazindikiritsa magulu otsatirawa a BC: 1) Zotupa za luminal, kusonyeza ER ndi / kapena mawu a PgR, amawerengera 75% ya BCs. HER2 kukulitsa, mosasamala kanthu za kuchuluka kwa index; 2) HER2 + zotupa zomwe ziri ER ndi PgR zoipa koma zimasonyeza HER2 kukulitsa. Gululi limapanga 10% ya zotupa za m'mawere; 3) Khansa ya m'mawere ya katatu (TNBC), yomwe sikuwonetsa ER ndi PgR kufotokozera ndi HER2 kukulitsa, imakhala pafupifupi 15% ya khansa ya m'mawere.2-4
Pakati pa ma subtypes a BC awa, kalasi ya chotupa ndi index yowonjezereka imayimira ma biomarkers omwe amalumikizana mwachindunji ndi modziyimira pawokha ndi kuwopsa kwa chotupa ndi kuneneratu.5,6
Kuphatikiza pa zinthu zomwe tazitchula pamwambapa, udindo wa kusintha kwa majini omwe amatsogolera ku chitukuko cha BC wakhala wofunika kwambiri m'zaka zingapo zapitazi.7 Pafupifupi 1 pa 10 zotupa za m'mawere zimatengera chifukwa cha kusintha kwa majeremusi m'ma jini enieni.8 Maphunziro awiri akuluakulu a epidemiological omwe amaphatikizapo oposa 180,000 amayi posachedwapa, TM TM, BCAARD, gulu la amayi asanu ndi atatu (180,000), gulu la TM B1, ABR BRCA2, CHK2, PALB2, RAD51C, ndi RAD51D) makamaka omwe ali ndi udindo wa cholowa cha BC. Pakati pa majiniwa, BRCA1 ndi BRCA2 (omwe amatchedwa BRCA1 / 2) adawonetsa mgwirizano wamphamvu kwambiri ndi chitukuko cha zotupa za m'mawere.9-12 Ndipotu, majeremusi amtundu wa BRCA1 ndi BRCA2 nthawi zambiri amawonjezeka kwambiri. kuphatikizapo ovarian, prostate, pancreatic, colorectal, ndi melanoma.Kuyambira zaka 13 mpaka zaka 80, kuchuluka kwa BC ndi 72% mwa amayi omwe ali ndi BRCA1 pathogenic variant (PV) ndi 69% mwa amayi omwe ali ndi BRCA2 PV.14
Zochititsa chidwi, zofalitsa zaposachedwa zikusonyeza kuti chiopsezo cha BC chimadalira mtundu wa PV. Ndipotu, poyerekeza ndi mitundu yosiyanasiyana ya pathogenic truncating, glaring missense mitundu, makamaka mu jini ya BRCA1, imagwirizana ndi kuchepetsa chiopsezo cha BC, makamaka kwa amayi achikulire.15
Kukhalapo kwa BRCA1 kapena BRCA2 PV kunkagwirizanitsidwa ndi zinthu zosiyanasiyana zamoyo komanso zachipatala. zotupa zochulukira.Zotupazi zimakhala zofala kwambiri mu lumen B ndipo nthawi zambiri zimachitika mwa anthu okalamba.16-18 Zodziwika bwino, kusintha kwa BRCA1 ndi BRCA2 kumawonjezera kukhudzidwa kwa mankhwala apadera, kuphatikizapo mchere wa platinamu ndi mankhwala omwe akugwiritsidwa ntchito monga poly(ADP-ribose) polymerase inhibitors (PARPi) .19,20
M'zaka zingapo zapitazi, kukhazikitsidwa kwa mibadwo yotsatira (NGS) muzochitika zachipatala kwathandiza kuti chiwerengero chowonjezeka cha odwala BC ayesedwe ndi maselo a khansa, kuphatikizapo BRCA1 / 2.21 Nthawi yomweyo, matanthauzo okhudzana ndi zochitika zenizeni zokhudzana ndi mbiri ya banja , chiwerengero cha anthu, ndi zizindikiro zachipatala kuti adziwe bwino anthu omwe ali ndi matenda a khansa232222222222. kusonkhanitsa pa BRCA1 / 2 kuyang'ana m'magulu enaake, kuwonetsa kusiyana pakati pa madera.24-27 Ngakhale kuti pali malipoti a BC cohort kumadzulo kwa Sicily, deta yocheperapo ikupezeka pa BRCA1 / 2 kuyang'ana kummawa kwa anthu a ku Sicily.28,29
Tikufotokoza apa zotsatira za kuwunika kwa majeremusi a BRCA1/2 mwa odwala BC ochokera kum'mawa kwa Sicily, kulumikizanso kukhalapo kwa kusintha kwa BRCA1 kapena BRCA2 ndi mbali zazikulu zachipatala za zotupazi.
Kafukufuku wobwerezabwereza adachitika ku "Center for Experimental Oncology and Hematology" pachipatala cha Policlinico.Rodolico - San Marco ku Catania.Kuyambira Januwale 2017 mpaka Marichi 2021, odwala 455 omwe ali ndi khansa ya m'mawere ndi ovarian, melanoma, pancreatic kapena prostate adatumizidwa ku kafukufuku wathu wamamolekyulu a BRCA2. Declaration of Helsinki, ndipo onse omwe adatenga nawo mbali adapereka chilolezo cholembedwa asanayambe kusanthula maselo.
Makhalidwe a histological ndi biological (ER, PgR, HER2 status, Ki-67, ndi grade) ya BC anayesedwa pa core biopsy kapena zitsanzo za opaleshoni, poganizira zigawo za chotupa zaukali zokha.Kutengera makhalidwe awa, BCs adayikidwa motere: luminal A (ER+ ndi/kapena PgR+, HER2-, BG+R , 7) HER2-, Ki-67≥20%), kuwala kwa B-HER2+ (ER ndi/kapena PgR+, HER2+), HER2+ (ER ndi PgR-, HER2+) kapena katatu (ER ndi PgR-, HER2-).
Asanawunike kusintha kwa BRCA1 ndi BRCA2, gulu lamitundu yosiyanasiyana kuphatikiza katswiri wa oncologist, katswiri wa chibadwa, ndi katswiri wa zamaganizo adachita kafukufuku wamtundu wa chotupa kwa wodwala aliyense kuti adziwe kupezeka kwa BRCA1 ndi/kapena BRCA1. kapena anthu omwe ali ndi chiopsezo chachikulu cha PV mu jini ya BRCA2. Kusankhidwa kwa odwala kunkachitidwa motsatira malangizo a Italy Society of Medical Oncology (AIOM) ndi malangizo a ku Sicilian. (ii) amuna omwe ali ndi BC; (iii) omwe ali ndi BC ndi OC; (iv) amayi omwe ali ndi BC <36 zaka, TNBC <60 zaka, kapena mayiko awiri BC <50 zaka; (v) mbiri yachipatala ya BC
Mitundu yonse ya mayina osiyanasiyana inatsatira ndondomeko zamakono za Human Genome Variation Consortium, zomwe zikupezeka pa intaneti (HGVS, http://www.hgvs.org/mutnomen) .Kufunika kwachipatala kwa mitundu yosiyanasiyana ya BRCA1/2 kunatanthauzidwa pogwiritsa ntchito gulu la International Consortium ENIGMA (Umboni-Based Network for Interpreting Allemcond.org) kuwunika ma database osiyanasiyana monga ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, ndi UMD. Gululi limaphatikizapo magulu asanu owopsa: benign (gulu I), mwina benign (gulu II), kusiyanasiyana kosadziwika bwino (VUS, gulu la III), mwina pathogenic (gulu IV), komanso anazeneza pathogenic (gulu IV), komanso anazenea ya VS). kapangidwe ka mapuloteni ndi ntchito, chida chodziwitsa chopezeka ndi database 30.32
Kupereka kufunikira kwachipatala ku VUS iliyonse, njira zolosera zam'mapuloteni zotsatirazi zidagwiritsidwa ntchito: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/G) ndi Align-GG (http://agvgd.hci.utah.edu/agvgd_input.php). Zosintha zomwe zidasankhidwa kukhala kalasi 1 ndi 2 zidawonedwa ngati zanyama.
Kutsatizana kwa Sanger kunatsimikizira kukhalapo kwa mtundu uliwonse wa matenda. Mwachidule, zoyambira zina zidapangidwira mtundu uliwonse womwe wapezeka pogwiritsa ntchito BRCA1 ndi BRCA2 gene reference sequences (NG_005905.2, NM_007294.3 ndi NG_012772.3, NM5. ndi Sanger kutsatizana.
Odwala omwe adapezeka kuti alibe jini ya BRCA1/2 adayesedwa ndi multiplex ligation-dependent probe amplification (MLPA) molingana ndi malangizo a wopanga kuti awone ngati pali ma genomic rearrangements (LGR) kutsata pafupifupi ma nucleotide a 60 m'litali.Probe amplification product, yopangidwa ndi ma PCR amplicon apadera, adawunikidwa ndi capillary electrophoresis ndi mapulogalamu a Cofalyser.Net molumikizana ndi matebulo oyenera a batch-Specific Cofalyser (www.mrcholland.com).
Zosintha zosankhidwa zachipatala ( histological grade ndi Ki-67% proliferation index) zinagwirizanitsidwa ndi kukhalapo kwa BRCA1 / 2 PV, kuwerengedwa pogwiritsa ntchito pulogalamu ya Prism v. 8.4 pogwiritsa ntchito mayeso enieni a Fisher poganiza kuti p-value <0.05 ndi yofunika.
Pakati pa Januwale 2017 ndi Marichi 2021, odwala 455 adapimidwa kuti ali ndi kusintha kwa majeremusi a BRCA1/2. Kuyezetsa kosinthika kunachitika ku Policlinico Hospital's Center for Experimental Oncology and Hematology. Malinga ndi malangizo a Sicilian (http://www.gurs.regione.sicilia.it.it/Indicep. Gennaio 2020), Rodolico waku Catania - San Marco" onse, odwala 389 Panali khansa ya m'mawere, khansa ya m'mawere 37, khansa ya pancreatic 16, khansa ya prostate 8 ndi melanoma 5. Kugawidwa kwa odwala malinga ndi mtundu wa khansa ndi zotsatira za kusanthula zikuwonetsedwa Chithunzi 1.
Chithunzi cha 1 chikuwonetsa tchati chotsatira chomwe chikuwonetsa mwachidule phunziroli.Odwala omwe ali ndi chifuwa, melanoma, pancreatic, prostate, kapena ovarian tumors adayesedwa kuti asinthe ma jini a BRCA1 ndi BRCA2.
Mafupipafupi: PVs, mitundu yosiyanasiyana ya pathogenic; VUS, kusiyanasiyana kosadziwika bwino; WT, mtundu wakuthengo wa BRCA1/2 mndandanda.
Tinasankha mosamala maphunziro athu pamagulu a khansa ya m'mawere. Odwalawo anali ndi zaka zapakati pa 49 (zosiyanasiyana 23-89) ndipo makamaka anali akazi (n = 376, kapena 97%).
Mwa maphunzirowa, 64 (17%) anali ndi masinthidwe a BRCA1 / 2 ndipo onse anali akazi. Makumi atatu ndi asanu (9%) anali ndi PV ndipo 29 (7.5%) anali ndi VUS. Seventeen (48.6%) mwa mitundu 35 ya pathogenic inachitika mu BRCA1 ndi 18 (51.4%) mu BRCA2, pamene . mu BRCA2 (Zithunzi 1 ndi 2) LGR sinalipo pakuwunika kwa MLPA.
Chithunzi 2. Kusanthula kwa kusintha kwa BRCA1 ndi BRCA2 kwa odwala khansa ya m'mawere a 389. (A) Kugawidwa kwa mitundu yosiyanasiyana ya pathogenic (PV) (yofiira), mitundu yosiyanasiyana ya kufunikira kosadziwika (VUS) (lalanje), ndi WT (buluu) mu 389 odwala khansa ya m'mawere; (B) 389 odwala khansa ya m'mawere Makumi atatu ndi asanu (9%) anali ndi BRCA1 / 2 mitundu ya pathogenic (PVs) . Pakati pawo, 17 (48.6%) anali BRCA1 PV zonyamulira (zofiira zakuda) ndi 18 (51.4%) zinali zonyamula BRCA2 (zofiira zofiira); (C) 29 (7.5%) mwa maphunziro 389 ananyamula VUS, 5 (17.2%) BRCA1 majini (mdima lalanje) ndi 24 (82.8%) BRCA2 majini (kuwala lalanje).
Mafupipafupi: PVs, mitundu yosiyanasiyana ya pathogenic; VUS, kusiyanasiyana kosadziwika bwino; WT, mtundu wakuthengo wa BRCA1/2 mndandanda.
Kenako tidafufuzanso kuchuluka kwa ma BC molecular subtypes mwa odwala omwe ali ndi BRCA1/2 PV. Kugawa kunaphatikizapo 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ ndi 13 (37.1%) pakati pa odwala 9 BRCA, 5% omwe anali ndi 9 BRCA, 5%. luminal B BC, 2 (11.8%) anali ndi matenda a HER2+, ndipo 10 (58.8%) anali ndi TNBC. Zotupa zopanda BRCA1 masinthidwe anali mwina luminal A kapena luminal B-HER2+ (Figure 3). (16.7%) TNBC ndi 2 (11.1%) anali luminal A (Chithunzi 3) .Palibe zotupa za HER2 + zomwe zinalipo mu gulu ili.Choncho, kusintha kwa BRCA1 kumakhala kofala kwa odwala TNBC, pamene kusintha kwa BRCA2 kumakhala kwakukulu mu lumen B anthu.
Chithunzi cha 3 Kuchuluka kwa khansa ya m'mawere kwa odwala omwe ali ndi mitundu yosiyanasiyana ya pathogenic mu BRCA1 ndi BRCA2.Histograms yosonyeza kugawa kwa BRCA1- (mdima wofiira) ndi BRCA2- (wofiira owala) PVs pakati pa ma molecular subtypes a odwala khansa ya m'mawere.Nambala zomwe zafotokozedwa mkati mwa bokosi lililonse zimayimira chiwerengero cha odwala omwe ali ndi BRCA1 ndi BRCA2 ya khansa ya m'mawere.
Mafupipafupi: PVs, mitundu yosiyanasiyana ya pathogenic; HER2 +, epidermal kukula factor receptor 2 zabwino; TNBC, khansa ya m'mawere yopanda katatu.
Pambuyo pake, tinayesa mtundu ndi jini ya BRCA1 ndi BRCA2 PVs.Mu BRCA1 PV, tinawona mitundu 7 ya nucleotide (SNVs), kuchotsedwa kwa 6, kubwereza kwa 3 ndi kuyika kwa 1. Kusintha kumodzi kokha (c.5522delG) kumaimira kupezedwa kwatsopano komwe kunapezeka mu PCA1V yodziwika kwambiri. c.5035_5039delCTAAT.Kusinthaku kumaphatikizapo kuchotsedwa kwa ma nucleotide asanu (CTAAT) mu BRCA1 exon 15, zomwe zimapangitsa kuti amino acid leucine alowe m'malo mwa tyrosine pa codon 1679, ndipo chifukwa cha kumasulira kwa frameshift ndi njira ina yonenedweratu imayimitsa puloteni imodzi yokha kusintha kwa proteni imodzi yokha. mlandu.Chochititsa chidwi, imodzi mwa ma PVs omwe adanenedwapo anali m'chigawo cha splice site consensus region (c.4357+1G>T) (Table 1).
Ponena za BRCA2 PV, tinawona kufufutidwa kwa 6, 6 SNVs ndi kubwereza kwa 2. Palibe zosintha zomwe zapezeka ndi zatsopano.Kusintha kutatu kunabwerezedwanso mwa anthu athu, c.428dup ndi c.8487 + 1G>A adawona mu maphunziro a 3, kutsatiridwa ndi c.5851_5854kubwerezabwereza kwa c. C mu exon 5 ya BRCA2, yonenedweratu kuti imapanga mapuloteni ochepa, osagwira ntchito. The c.8487 + 1G> Kusintha kumachitika m'chigawo cha intronic cha BRCA2 intron 19 (± 1,2) ndipo kumakhudza kutsatizana kwa splicing, zomwe zimapangitsa kusintha kwa splicing kapena mapuloteni. c.5851_5854delAGTT kusiyanasiyana kwa pathogenic kumachitika chifukwa cha kuchotsedwa kwa 4-nucleotide ku nucleotide malo 5851 mpaka 5854 mu coding exon 10 ya jini ya BRCA2 ndipo kumabweretsa kumasulira kosinthika ndi njira ina yodziwikiratu yoyimitsa (p.S1951WF monga momwe tafotokozera kale). c.631G>A ndi c.7008-2A>T adapezeka mwa wodwala yemweyo.34 Kusintha koyamba kumaphatikizapo kulowetsedwa kwa adenosine (A) mu BRCA2 exon 7 ndi guanine (G) yomwe ili ndi nucleotide yomwe imapangitsa kusintha kwa valine ku isoleucine pa codon 211 ndi kusintha kwamino acidIyi ndi yofanana ndi amino acid aminoR amino acid. splicing.Kusiyana kwachiwiri kumapezeka m'chigawo cha intronic ndipo kumapangitsa kuti pawiri A ku thymine (T) kulowe m'malo pamaso pa exon 13 ya jini encoding BRCA2. Kusintha kwa c.7008-2A>T kungapangitse zolemba zambiri zautali wosiyana. Komanso, mu gulu la BRCA2 PVs, 8 kusintha kwa 2% mu intro2.
Kenako tinajambula masinthidwe a BRCA1/2 owononga m'madera ogwirira ntchito komanso zigawo zomanga mapuloteni (mkuyu. 4) .Mu jini ya BRCA1, 50% ya PVs inali m'chigawo cha masango a khansa ya m'mawere (BCCR), pamene 22% ya masinthidwewo anali m'chigawo cha ovarian khansa cluster region (OCCR) (Mkuyu 30 BRCA5A mu PV 7A). chigawo cha BCCR ndi 42.8% ya masinthidwewo anali mu OCCR (mkuyu 4B) .Kenako, tinayesa malo a PV mkati mwa BRCA1 ndi BRCA2 madera a mapuloteni.Kwa mapuloteni a BRCA1, tinapeza ma PV atatu mu madera a loop ndi coil coil, ndi masinthidwe awiri mu BRCT4 domain mapped, BRCT4 mapped protein. ku BRC kubwereza domain, pamene 3 intronic ndi 3 zosintha zachilendo zinapezeka mu oligo / oligosaccharide-binding (OB) ndi nsanja (T) madera (Chithunzi 4B).
Chithunzi cha 4 Schematic chifaniziro cha BRCA1 ndi BRCA2 mapuloteni ndi kumasulira kwa mitundu ya tizilombo toyambitsa matenda.Chiwerengerochi chikuwonetsa kugawidwa kwa BRCA1 (A) ndi BRCA2 (B) mitundu ya pathogenic mwa odwala khansa ya m'mawere. Kusintha kwachilendo kumawonetsedwa mumtambo wa buluu, pamene zosiyana zowonongeka zikuwonetsedwa mu lalanje.Kutalika kwa bar kumayimira chiwerengero cha milandu. Puloteni ya BRCA1 ili ndi malo ozungulira (RING) ndi ndondomeko ya nyukiliya (NLS), malo ozungulira-coil, ndi SQ/TQ cluster domain (SCD), ndi BRCA1 C-terminal domain (BRCT) . folds, a tower domain (T), and An NLS on the C side.Madera otchedwa Breast Cancer Cluster Region (BCCR) ndi Ovarian Cancer Cluster Region (OCCR) akuwonetsedwa pansi.*Zikuyimira masinthidwe omwe amazindikira ma codon oyimitsa.
Kenako tinafufuza za BC clinicopathological features zomwe zingagwirizane ndi kukhalapo kwa BRCA1 / 2 PV. Complete clinic records was available for 181 BRCA1 / 2-negative odwala (osakhala onyamula) ndi onse onyamula (n = 35) .
Tinawerengera kugawidwa kwa Ki-67 pogwiritsa ntchito wapakatikati wa gulu lathu (25%, range <10-90%).Mitu yomwe ili ndi Ki-67 <25% inatanthauzidwa kuti "otsika Ki-67", pamene anthu omwe ali ndi makhalidwe ≥ 25% ankaonedwa kuti ndi "Ki-67" yapamwamba kwambiri. BRCA1 PV zonyamulira (mkuyu 5A).
Chithunzi 5 Kulumikizana kwa Ki-67 ndi kugawa kwa kalasi kwa amayi omwe ali ndi khansa ya m'mawere omwe ali ndi BRCA1 ndi BRCA2 PVs (A) Boxplot yosonyeza zapakatikati za Ki-67 mwa odwala 181 osanyamula BC motsutsana ndi BRCA1 (18) kapena BRCA2 (17) odwala PV.P. kugawa kwa odwala khansa ya BC m'magulu a histological grade (G2 ndi G3) molingana ndi BRCA1 ndi BRCA2 mutation status (mitu ya WT, BRCA1 ndi BRCA2 PVs carriers).
Momwemonso, tinapenda ngati kalasi ya chotupa ikugwirizana ndi kukhalapo kwa BRCA1/2 PV. Popeza G1 BC kunalibe m’chiŵerengero chathu, tinagawa odwalawo m’magulu awiri (G2 kapena G3) . (p<0.005) (Chithunzi 5B).
Kupita patsogolo kwa ukadaulo wotsatizana wa DNA kwathandiza kupita patsogolo kopitilira muyeso pakuyesa kwa majini a BRCA1/2, zomwe ndizofunikira kwambiri kwa odwala omwe ali ndi mbiri ya banja la khansa. 37 Mu Italy, mlingo wa BRCA1/2 PVs unachokera ku 8% mpaka 37%, kusonyeza kusiyana kwakukulu pakati pa mayiko.38,39 Ndi anthu pafupifupi 5 miliyoni, Sicily ndi dera lachisanu lalikulu ku Italy malinga ndi chiwerengero cha anthu. chilumba.
Phunziro lathu ndi limodzi mwa lipoti loyamba la zochitika za BRCA1 / 2 PV kwa odwala BC kum'maŵa kwa Sicily.28 Tinayang'ana kafukufuku wathu pa BC, chifukwa ichi ndi matenda omwe amapezeka kwambiri m'gulu lathu.
Poyesa odwala 389 BC, 9% ananyamula BRCA1 / 2 PVs, yogawidwa mofanana pakati pa BRCA1 ndi BRCA2. Zotsatirazi zimagwirizana ndi zomwe zinanenedwa kale ku Italy.28 Chochititsa chidwi n'chakuti, 3% (13 / 389) ya gulu lathu anali amuna.Mlingo uwu ndi wapamwamba kusiyana ndi kuyembekezera kwa BRCA1 ndi BRCA2. BRCA1/2 mutation risk.Komabe, palibe mmodzi wa amunawa amene anapanga BRCA1/2 PV, kotero iwo anali ofuna kufufuza mowonjezereka kwa maselo kuti athetse kukhalapo kwa masinthidwe ang'onoang'ono monga PALB2, RAD51C ndi D, pakati pa zina. umboni.28,41,42
Pamene tidasanthula kagawidwe ka BC molecular subtypes mu BRCA1/2 akazi osinthika, tidatsimikizira mayanjano odziwika pakati pa TNBC ndi BRCA1 PV (58.8%) komanso pakati pa luminal B BC ndi BRCA2 PV (55.6%).16,43 Zotupa za luminal A ndi HER2+ mu BRCA1 ndi BRCA1 zonyamulira za BRCA2 ndi zonyamula 6 zonyamula BRCA2 zomwe zilipo.
Kenako timaganizira za mtundu ndi malo a BRCA1/2 PV. Mu gulu lathu, BRCA1 PV yodziwika kwambiri inali c.5035_5039delCTAAT.Ngakhale Incorvaia et al. sanafotokoze kusiyana kumeneku mu gulu lawo la Sicilian, olemba ena adanena kuti ndi majeremusi a BRCA1 PV.34 Ma PV angapo a BRCA1 anapezeka m'gulu lathu - mwachitsanzo c.181T>G, c.514del, c.3253dupA ndi c.5266dupC - zomwe zapezedwa ziwiri BRCA1 mu Sici. (c.181T> G ndi c.5266dupC) amapezeka kawirikawiri ku Ashkenazi Ayuda a Kum'mawa ndi Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian ndi German ), 44,45 ndipo, ku United States ndi Argentina, posachedwapa anatanthauzidwa kuti "kusiyana kwa majeremusi obwerezabwereza" BCdel 4 odwala omwe kale anali ndi OCdel 4 BC5. mu 8 odwala khansa ya m'mawere ochokera kumpoto kwa Sicily ku Palermo ndi Messina.Chochititsa chidwi, ngakhale Incorvaia et al. anapeza kusiyana kwa c.3253dupA m'mabanja ena ku Catania.28 Ma BRCA2 PV oimira kwambiri ndi c.428dup, c.5851_5854delAGTT ndi intronic kusiyana c.8487+1G>A, zomwe zafotokozedwa mwatsatanetsatane 28 mwa wodwala ku Palermo ndi c.52AG5 c. adawonedwa m'mabanja a kumpoto chakumadzulo kwa Sicily, makamaka m'madera a Trapani ndi Palermo, pamene c.5851_5854delAGTT PV inkawonedwa m'mabanja kumpoto chakumadzulo kwa Sicily.Zosiyana za 8487 + 1G>A zinali zofala kwambiri pa maphunziro ochokera ku Messina, Palermo, ndi Caltanissetta.28 Rebbeck et al. m'mbuyomu adalongosola kusintha kwa c.5851_5854delAGTT ku Colombia.37 Wina BRCA2 PV, c.631 + 1G>A, wapezeka mu BC ndi OC odwala ochokera ku Sicily (Agrigento, Siracusa ndi Ragusa) .28 Mwachidziwitso, tinawona kukhalapo kwa mitundu iwiri ya BRCA2 c.6 ndi 31G2 (BRCA2>A) c.7008-2A>T) mu odwala omwewo, omwe timaganiza kuti tasiyanitsidwa ndi cis mode, monga momwe tafotokozera kale monga choncho.34,46 Kusintha kwa BRCA2 uble kumawoneka kawirikawiri m'chigawo cha Italy ndipo kunapezeka kuti kumayambitsa ma codons oima msanga, omwe amakhudza mthenga wa RNA splicing ndikupangitsa kuti BRCA2 iwonongeke, puloteni ya BRCA2,8.
Tinapanganso mapu a BRCA1 ndi BRCA2 PVs m'magawo a OCCR ndi BCCR a zigawo za mapuloteni ndi majini. Maderawa adafotokozedwa ndi Rebbeck et al. monga malo owopsa a khansa ya ovary ndi khansa ya m'mawere, motero.49 Komabe, umboni wokhudzana ndi kugwirizana pakati pa malo a mitundu yosiyanasiyana ya majeremusi ndi chiopsezo cha khansa ya m'mawere kapena yamchiberekero imakhalabe yotsutsana. madera a putative OCCR ndi BCCR ndi zizindikiro za BC. Izi zikhoza kukhala chifukwa cha chiwerengero chochepa cha odwala omwe ali ndi kusintha kwa BRCA1 / 2. Kuchokera ku mapuloteni a mapuloteni, BRCA1 PVs amagawidwa pamodzi ndi mapuloteni onse, ndipo kusintha kwa BRCA2 kumapezeka makamaka mu BRC kubwereza domain.
Potsirizira pake, tinagwirizanitsa mbali zachipatala za BC ndi BRCA1 / 2 PV. Chifukwa cha chiwerengero chochepa cha odwala omwe akuphatikizidwa, tinangopeza mgwirizano waukulu pakati pa Ki-67 ndi kalasi ya chotupa. "okwera" ndi "otsika" Ki-67 ndi 20%.Komabe, izi sizikugwira ntchito kwa odwala athu osinthika a BRCA1/2, omwe ali ndi mtengo wapakatikati wa Ki-67 wa 25%.Mchitidwewu pamiyezo yapamwamba ya Ki-67 ukhoza kufotokozedwa ndi kufalikira kwa magulu athu ounikira a B ndi TNBC, omwe owerengeka ochepa chabe amawonetsa kuti zotupa za Ki-6 zinalipo. (25-30%) akhoza kugwirizanitsa bwino odwala malinga ndi momwe amachitira.53,54 Kuchokera pazotsatira za kusanthula kwathu, kugwirizanitsa kwakukulu sikudabwitsa.Kumachitika pakati pa Ki-67 yapamwamba ndi magiredi ndi kukhalapo kwa BRCA1 PV. Ndipotu, zotupa zokhudzana ndi BRCA1 ndizofanana ndi TNBC ndipo zimasonyeza zinthu zambiri zaukali.16,17,17.
Pomaliza, phunziroli limapereka lipoti la kusintha kwa kusintha kwa BRCA1 / 2 mu gulu la BC kuchokera kummawa kwa Sicily.Ponseponse, zomwe tapeza zikugwirizana ndi umboni womwe ulipo kale, pokhudzana ndi kusintha kwa masinthidwe ndi zochitika zachipatala mu BC. a PVs omwe ali osiyana komanso ocheperapo kusiyana ndi BRCA1 / 2. Izi zidzalola kuzindikiritsa ndi kuyang'anira bwino chiwerengero cha anthu omwe ali pachiopsezo cha khansa chifukwa cha kusintha kwa majini.
Tidatsimikizira kuti odwala adasaina chilolezo chodziwitsidwa kuti atulutse zitsanzo zawo zotupa mosadziwika bwino pazolinga zofufuza.Odwala onse adasaina chilolezo chodziwitsidwa molingana ndi Declaration of Helsinki.Malinga ndi ndondomeko ya AOU Policlinico "G.Rodolico - S.Marco", kafukufukuyu sanakhululukidwe kuwunikanso kwamakhalidwe chifukwa kusanthula kwa BRCA1/2 kunachitikanso molingana ndi chilolezo cha odwala olembedwa komanso chilolezo cha odwala. deta pazolinga zofufuzira.
Tikuthokoza Prof. Paolo Vigneri chifukwa cha thandizo lake posamalira odwala khansa ya m'mawere monga momwe Komiti ya Ethics inapempha.
Federica Martorana akufotokoza ulemu kuchokera ku Istituto Gentili, Eli Lilly, Novartis, Pfizer.Olemba ena amalengeza kuti palibe mikangano ya chidwi pa ntchitoyi.
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Nthawi yotumiza: Apr-15-2022
